Rheumatoid arthritis (hereinafter, may be referred to as just “RA”), whose main symptom is multiple erosive arthritis, is a systemic inflammatory disease whose cause is unknown and which affects multiple organs at once. RA develops chronically while alternating between remission and exacerbation, causes the damage and deformation of joints if left untreated, and finally shows the dysfunction of motor organs. In some cases, RA is life-threatening. Therefore, RA patients suffer physically and mentally from heavy pain all their lives.
RA shows a wide variety of symptoms. For the diagnosis of RA, the diagnostic criteria by the American College of Rheumatology have been widely used. However, the RA onset is slow and usually takes several weeks to several months. The percentage positive of a rheumatoid factor, which is used as an objective index in the diagnostic criteria adopted by the American College of Rheumatology, is about 33% within three months and about 88% in twelve months and longer (Treatment, Vol. 73, No. 3, pp23-27, in 1991), and a definite diagnosis of RA has not been achieved. Consequently, approaches to the diagnosis of rheumatoid arthritis have been made by detecting rheumatoid arthritis-related IgM antibodies in patient sera that react with a recombinant antigen (See Japanese Laid-Open Patent Publication No. 513257/1998 (Tokukaihei 10-513257) published on Dec. 15, 1998).
Further, in the therapy for RA, therapeutic measures to be selected usually differ depending on a progressing course in the condition of RA pathema. Generally, in an early stage when a definite diagnosis cannot be given, non-steroidal anti-inflammatory drug (NSAID) is administered. In the case when the definite diagnosis can be given, disease modifying anti-rheumatic drugs (DMARD) is administered in addition to NSAID. Especially in the early stage of the RA onset, a definite diagnosis is difficult to be given. Under the present circumstances, discrimination from other rheumatoid diseases including collagen disease is carried out together with a careful observation of the progress while NSAID is administered. When symptoms progress further, steroid drug may be administered, and a medical therapy for the enhancement of pain relief is carried out together with a physical therapy and an orthotic therapy for the maintenance and recovery of joint function. Furthermore, when the joint damage causes inconvenience in a daily life, a surgical therapy may be carried out.
Aspects of arthritis and joint damage causing RA, particularly the pathological courses thereof, have been elucidated gradually through various research works. RA is induced by the concomitant participation of numerous causative factors including living environment and is then exacerbated progressively to the stage of apparent diseases; therefore, the interactive mechanism per se of such numerous factors should be elucidated for accurate characterization and appropriate therapeutic management of the disease. The prevalence of RA is not more than 1% on a global scale (New England Journal of Medicine, Vol. 322, p. 1277-1289, in 1990), but the frequency of the disease is about 8 times greater in sibs of the patients with the disease (Cell, Vol. 85, p. 311-318, in 1996). Hence, it is predicted that a certain genetic factor may serve as one of the causative factors. Since an environment is regarded as one of the causative factors, previous knowledge of the RA onset possibility makes it possible to delay and prevent the RA onset by attentions to the diet, virus infection, stresses, etc. in daily life. Furthermore, an early diagnosis and a proper treatment in early stages can delay the course of RA and expect the improvement of prognosis.
In International Patent Publication WO98/51791 (published on Nov. 19, 1998), the inventors of the present application have conducted the linkage analysis using microsatellite markers to RA patients and their sibs and specified three loci where causative genes of rheumatoid arthritis are located. The following causative genes have been identified:
(1) A causative gene for rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome 1 to which the microsatellite markers D1S214 and/or D1S253 are hybridized.
(2) A causative gene for rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome 8 to which the microsatellite marker D8S556 is hybridized.
(3) A causative gene for rheumatoid arthritis, which gene is located within ±1 centimorgan on a DNA sequence on human chromosome X to which the microsatellite markers DXS1001, DXS1047, DXS1205, DXS1227 and/or DXS1232 are hybridized.
As described above, it was found that the loci of disease susceptibility genes of rheumatoid arthritis locate on chromosomes 1, 8, and X. Among the chromosomes, the disease susceptibility genes of RA have been identified for chromosomes 1 and X, but not for chromosome 8.
In the view of this, objects of the present invention is to identify the disease susceptibility genes of rheumatoid arthritis located on human chromosome 8, and to provide (i) an evaluation (diagnosing) method for evaluating onset or onset possibility of RA with high accuracy by detecting whether mutation of the gene or mutation of a protein that is translation product thereof, is present or absent, and (ii) evaluation (diagnosing) kit thereof. Another object of the present invention is to provide a remedy and a curing medicine effective for RA patients having mutation in the disease susceptibility gene for rheumatoid arthritis.